The present understanding of the underlying pathophysiological mechanism of acute secretory diarrhea is growing steadily. Secretory diarrhea can accompany gastrointestinal disorders such as inflammatory bowel disease. Acute diarrhea is a world-wide problem, and easily accounts for over a million deaths per year. Medical and pharmacological textbooks generally delineate two classifications for anti-diarrheal medications. The first group are known as astringents. The second group are opium derivatives. While such medications have met with some degree of success, it is an alarming fact that drug development specifically targeting diarrheal disease has been, until recently, almost nonexistent.
Probably the most significant event in the treatment of diarrheal disease in the past one hundred years has been the use of oral glucose-electrolyte solutions. But, there still is a need recognized by world-wide health organizations for continuing effort in diarrhea therapies.
Recent studies of electrolyte transport by intestinal mucosa have provided valuable information concerning the regulation of biochemical events involved in diarrhea. While there is still much refinement work needed, it has now become apparent that a method of treatment of diarrhea would be to control electrolyte transport, particularly chloride secretion.
In chloride secretion, chloride enters the cell across the basolateral membrane on a cotransporter that is coupled to entry of Na.sup.+ and K.sup.+. The entry step is electrically neutral because the charge on the anion is balanced by the charges on the cations. The cotransporter accumulates Cl.sup.- in the cell at a value greater than that predicted for electro-chemical equilibrium. Removal of Na.sup.+ from the submucosal solution or addition of a loop diuretic (furosemide or bumetanide) inhibits Cl.sup.- accumulation in the cell, thereby inhibiting Cl.sup.- secretion. Na-K-ATPase in the basolateral membrane maintains the Na.sup.+ concentration within the cell lower than that in the submucosal solution; that gradient across the basolateral membrane provides the energy required to pull Cl.sup.- and K.sup.+ into the cell. As the pump hydrolyzes ATP, it drives Na.sup.+ out of the cell and K.sup.+ into the cell; the pump maintains a low intracellular Na.sup.+ (approximately 20 mmol/L) and a high intracellular K.sup.+ (approximately 150 mmol/L). Thus, by maintaining a low intracellular Na.sup.+ concentration, the Na-K-ATPase provides the energy for both Cl.sup.- secretion and Na.sup.+ absorption.
Evidence that the Na.sup.+ pump is located only on the basolateral side of the cells came from the observation that ouabain, an inhibitor of Na-K-ATPase, inhibits transport only when added to the submucosal surface; addition to the mucosal side had no effect. Studies of ouabain binding also showed localization over the basolateral cell membrane. Although the activity of the Na.sup.+ pump is required for transepithelial transport, that activity dose not directly control the rate of transport. Rather, the rate is primarily controlled by the ion channels present in both cell membranes and, possibly, by the Cl.sup.- entry step at the basolateral membrane.
Potassium, which enters the cell on the Na.sup.+ pump (and may also do so in the Na.sup.+ -K.sup.+ -Cl.sup.- entry step), must exit across the basolateral membrane because there is very little K.sup.+ secretion in most secretory epithelia. K.sup.+ accumulates in the cell above electrochemical equilibrium and thus can flow passively out of the cell through basolateral K.sup.+ channels. The patch-clap technique, combined with studies of transepithelial current and isotope fluxes, revealed that K.sup.+ can exit across the basolateral membrane through at least two types of K.sup.+ channels, those gated by Ca.sup.2+ and those gated by some other factor, probably cAMP.
This exit of K.sup.+ across the basolateral membrane plays two important physiologic roles. First, it maintains a negative intracellular voltage, which is important for driving Cl.sup.- exit across the apical membrane. Second, it prevents cell swelling, which would otherwise result from entry of K.sup.+. Thus, the activity of the basolateral K.sup.+ channels contributes to the overall rate of transport.
The apical membrane of airway epithelial cells contains Cl.sup.- channels, which, when activated, provide pores through which Cl.sup.- can move passively, down a favorable electrochemical gradient into the mucosal solution. Recent work indicates that the cystic fibrosis transmembrane conductance regulator (CFTR) is the Cl.sup.- channel responsible for cAMP-mediated Cl.sup.- secretion. Addition of a hormone, such as a .beta.-adrenergic agonist, or a toxin, such as cholera toxin, leads to an increase in cAMP, activation of cAMP-dependent protein kinase, and phosphorylation of the CFTR Cl.sup.- channel, which causes the channel to open. An increase in cell Ca.sup.2+ can also activate different apical membrane channels. Phosphorylation by protein kinase C can either open or shut Cl.sup.- channels in the apical membrane.
Accordingly a primary objective of the present invention is to develop an effective treatment for secretory diarrhea.
Another objective of the present invention is to develop an effective treatment for secretory diarrhea that involves the electrolyte transport mechanism, which is the underlying cause of secretory diarrhea.
Another objective of the present invention is to provide a treatment for secretory diarrhea, which involves use of agents that block the CFTR chloride channel, these agents include sulfonylureas and related agents that have been called potassium channel blockers and openers; prevention of the chloride channel transfer mechanism will prevent diseases involving secretion, such as diarrhea.
Another objective of the present invention is to provide a pharmaceutically acceptable composition, especially adapted for oral dosage, which contains some of the active compounds of the present invention in a pharmaceutically acceptable oral dosage carrier.
The method and manner of accomplishing each of the above objectives, as well as others, will become apparent from the detailed description of the invention which follows hereinafter.